Along with the voices of Brad Pitt, Tina Fey and Jonah Hill, the DreamWorks Animation release has Ferrell's title character hatching a scheme to fill the void in his life after he finally defeats his superhero nemesis.

Robert Downey Jr. and Zach Galifianakis' road-trip comedy, "Due Date," opened at a strong No. 2 with $33.5 million. The Warner Bros. romp features the two stars as mismatched traveling companions who hit the highway from Atlanta to Los Angeles.

Tyler Perry's drama "For Colored Girls," whose ensemble cast features Janet Jackson and Whoopi Goldberg, premiered solidly in third-place with $20.1 million. The Lionsgate release is based on Ntozake Shange's play "for colored girls who have considered suicide/ when the rainbow is enuf."

While "Megamind" drew big family crowds on Saturday and Sunday, it also was the top draw on Friday, bringing in large numbers of adults without children, said Anne Globe, head of marketing for DreamWorks Animation.

"For us to be No. 1 on Friday, it showed we did have a lot of appeal to teens, tweens and the date crowd," Globe said.

The three newcomers combined for a $100 million haul, providing a big weekend for Hollywood, whose revenues have been lagging for most of the fall season.

Overall revenues came in at $155 million, up 29.5 percent from the same weekend a year ago, when "A Christmas Carol" led with $30.1 million, according to box-office tracker Hollywood.com.

The weekend also provided an early jump on the holidays, when big releases include the latest in the "Harry Potter," "Meet the Parents" and "Chronicles of Narnia" franchises.

"Just like the first weekend in May has become the kickoff to the summer season, the first weekend in November has become the start of the holiday movie season," said Hollywood.com analyst Paul Dergarabedian. "Pound for pound, the coming weeks are just as important as the summer movie season."

Hollywood also had good results from some films opening in limited release. Fox Searchlight's survival story, "127 Hours," took in $265,925 at four theaters, averaging a whopping $66,481 a cinema. That compared to $12,082 in 3,944 theaters for "Megamind."

Directed by Danny Boyle ("Slumdog Millionaire"), "127 Hours" stars James Franco in the real-life story of a mountain climber trapped for more than five days in a narrow canyon after a falling boulder pins his arm.

Another real-life drama, Summit Entertainment's political saga "Fair Game," took in $700,000 in 46 theaters for a $15,217 average. "Fair Game" features Naomi Watts and Sean Penn in the story of Valerie Plame, a CIA operative whose cover was blown by a Bush administration leak.

"Fair Game" and "127 Hours" gradually expand to more theaters in the coming weeks.

Directed by Todd Phillips, "Due Date" came in well below his previous movie, last year's blockbuster "The Hangover," which opened with $45 million and went on to top the domestic box-office charts for R-rated comedies with $277 million.

But "The Hangover" played to a younger audience during the busier summer season.

"That was June, this is November. There are so many reasons that don't make it apples to apples," said Jeff Goldstein, Warner Bros. general sales manager.

Lionsgate hopes "For Colored Girls" will have staying power at the box office and broaden its audience, which was mostly older black women, with 87 percent of the crowd over 25.

"You always want the biggest opening you can get, but the reality is, older-skewing films don't open as big, simply because older audiences don't flock to cinemas over opening weekend," said David Spitz, head of distribution for Lionsgate.

Estimated ticket sales for Friday through Sunday at U.S. and Canadian theaters, according to Hollywood.com. Final figures will be released Monday.